Developmentally regulated transcription factors drive developmental gene programs that result in embryo formation and the birth, proliferation, growth, migration, and differentiation of the cells that eventually make up the different tissues of the body. This involves the expression and repression of many genes including those whose protein products act as regulators of this process as signal molecules. Some of these signal molecules may be re-expressed in the adult after injury, or the failure of such re-expression may relate to the failure of replacement cells to survive, grow, or regenerate after injury. Some of the signal molecules may act in pathological situations to either promote or suppress abnormal growth or function. These signal molecules, acting on specific transmembrane receptors, may serve as cell fate determinants, survival factors, growth factors, guidance cues, or differentiation factors, and many may have potential therapeutic roles as biological agents beyond their specific involvement in development. Such factors can have biological activity both in vivo and for maintaining cultured cells in vitro, or for converting pluripotent stem cells into specific neuronal or non-neuronal subtypes. Similarly, mimicking the action of these signal molecules by activating their membrane bound receptors or the intracellular signal transduction pathways coupled to their receptors, may also have therapeutic potential.
The transforming growth factor beta (TGF-β) superfamily ligands are central to many signal transduction pathways that control the growth and differentiation of mammalian cells. These ligands and pathways have been implicated in the control of a variety of cellular processes ranging from early vertebrate development to carcinogenesis where specific TGF-β ligands are involved in cell specification, differentiation, proliferation, patterning, and migration.
The TGF-β signaling pathways may be subdivided along two major branches—the TGF-β/Activin/Nodal pathways and the BMP/GDF pathways. The TGF-β/activin/nodal subfamily of ligands contribute to the specification of endoderm and mesoderm in pregastrula embryos and at gastrula stages, to dorsal mesoderm formation and anterior-posterior patterning. Later, they influence the body axis and dorsal-ventral patterning of the nervous system. Bone morphogenetic proteins (BMPs), the second major subfamily of TGF-β ligands contribute to the ventralization of germ layers in the early embryo, suppressing the default neural cell fate of the ectoderm. Neural induction follows formation of the organizer in the dorsal mesoderm which generates inhibitory signals that interrupt BMP signaling in the ectoderm leading to a separation of neural from epidermal territories. BMPs also participate later in development in the formation and patterning of the neural crest, heart, blood, kidney, limb, muscle, and skeletal system.